The present invention relates to novel dioxinoindole and thienobenzodioxin compounds which have affinity for 5-HT1A and/or D2-like (D2, D3 and/or D4 sub-types) receptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson""s disease, obesity, hypertension, Tourette""s syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer""s disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, and spasticity.
WO9507274 discloses compounds of the general formula 
in which R1 is selected from a number of substituents or two adjacent R1 groups together with the carbon atoms to which they are attached form a fused benz ring, A and B are xe2x80x94Oxe2x80x94 or methylene, U is an alkylene chain, Q is selected from the following: 
xe2x80x94Nxe2x80x94Vxe2x80x2xe2x80x94Nxe2x80x94
and T is an optionally substituted aromatic group optionally containing one or more N atoms. These compounds are described as being useful in the treatment of central nervous system disorders.
The present invention provides compounds of formula I 
including pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates, or other mixtures of enantiomers, in which
A is methylene or xe2x80x94Oxe2x80x94;
B is methylene or xe2x80x94Oxe2x80x94;
G1xe2x80x94G2xe2x80x94G3 represent xe2x80x94N(Rxe2x80x2)xe2x80x94C(Rxe2x80x3)xe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90C(Rxe2x80x3)xe2x80x94N(Rxe2x80x2)xe2x80x94, xe2x80x94N(Rxe2x80x2)xe2x80x94C(Rxe2x80x3)xe2x80x94C(Rxe2x80x2xe2x80x3)xe2x80x94, xe2x80x94C(Rxe2x80x2xe2x80x3)xe2x95x90C(Rxe2x80x2)xe2x80x94N(Rxe2x80x2)xe2x80x94, xe2x80x94N(Rxe2x80x2)xe2x80x94Nxe2x95x90C(Rxe2x80x3)xe2x80x94, xe2x80x94C(Rxe2x80x3)xe2x95x90Nxe2x80x94N(Rxe2x80x2)xe2x80x94, xe2x80x94N(Rxe2x80x2)xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94N(Rxe2x80x2)xe2x80x94, xe2x80x94Nxe2x95x90C(Rxe2x80x3)xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x95x90C(Rxe2x80x3)xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94C(Rxe2x80x3)xe2x95x90Nxe2x80x94, xe2x80x94Sxe2x80x94C(Rxe2x80x3)xe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94Nxe2x95x90C(Rxe2x80x3)xe2x80x94, xe2x80x94Sxe2x80x94Nxe2x95x90C(Rxe2x80x3)xe2x80x94, xe2x80x94C(Rxe2x80x3)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(Rxe2x80x3)xe2x95x90Nxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94, xe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94, xe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(Rxe2x80x2)(Rxe2x80x2)xe2x80x94Oxe2x80x94 wherein
Rxe2x80x2 is H or an alkyl group containing 1 to 3 carbon atoms; and
Rxe2x80x3 and Rxe2x80x2xe2x80x3, which are the same or different, are H; halo; an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo; carboxy; an alkanoyl group containing 1 to 6 carbon atoms; an alkoxycarbonyl group in which the alkoxy group contains 1 to 3 carbon atoms; formyl; cyano; or a carbamoyl group or carbamoylmethyl group each optionally N-substituted by one or two alkyl groups, which may be the same or different, each containing 1 to 3 carbon atoms;
g is 0, 1 or 2;
R1 represents an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo; an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo; halo; or an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo; the substituents represented by R1 being the same or different when g is 2;
R2 is H or an alkyl group containing 1 to 3 carbon atoms;
R3 and R4, which are the same or different, are H, or an alkyl group containing 1 to 3 carbon atoms;
U is an alkylene chain containing 1 to 3 carbon atoms, optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms;
Q represents a divalent group of formula IIa, IIb or IIc 
xe2x80x83in which V is (CH2)n, wherein n is 0, 1, 2 or 3, optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms;
Vxe2x80x2 is an alkylene chain containing 2 to 6 carbon atoms, optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms;
E is an alkylene chain containing 0 to 2 carbon atoms and Exe2x80x2 is an alkylene chain containing 1 to 4 carbon atoms provided that the total number of carbon atoms in E and Exe2x80x2 amounts to 3 or 4; and
R5 and R6, which may be the same or different, are H or an alkyl group containing 1 to 4 carbon atoms; and
T represents phenyl, 1- or 2-naphthyl, 1-naphth[2,1-d][
1,2,3]oxadiazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 7-benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or 7-benzo[b]thiophenyl, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-2-yl, 5-tetrazolyl, 2-, 3- or 4-quinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl each of which may be optionally substituted by one or more substituents selected from a) halo, b) an alkyl group containing 1 to 4 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or carbamoylmethyl group each optionally N-substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, I) a sulphamoyl or sulphamoylmethyl group each optionally N-substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, m) an amino group optionally substituted by one or two alkyl groups each containing 1 to 5 carbon atoms, n) 1-pyrrolidinyl or 1-piperidinyl, o) nitro or p) acetamido.
In preferred compounds of formula I, A is xe2x80x94Oxe2x80x94.
In preferred compounds of formula I, B is xe2x80x94Oxe2x80x94.
In more preferred compounds of formula I, both A and B are xe2x80x94Oxe2x80x94.
In preferred compounds of formula I, g is 0 or 1. When g is 1, R1 is preferably halo or an alkyl group containing 1 to 3 carbon atoms. In more preferred compounds of formula I, g is 0.
In preferred compounds of formula I, G1xe2x80x94G2xe2x80x94G3 are xe2x80x94N(Rxe2x80x2)xe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94; xe2x80x94Sxe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94, xe2x80x94N(Rxe2x80x2)xe2x80x94Nxe2x95x90C(Rxe2x80x3)xe2x80x94,. xe2x80x94Oxe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94, or xe2x80x94Oxe2x80x94C(Rxe2x80x2)(Rxe2x80x2)xe2x80x94Oxe2x80x94. Preferably, Rxe2x80x2 is H, Rxe2x80x3 is H or alkoxycarbonyl (more preferably H or ethoxycarbonyl), and Rxe2x80x2xe2x80x3 is H or halo (more preferably H or chloro). In more preferred compounds of formula I, G1xe2x80x94G2xe2x80x94G3 are xe2x80x94Oxe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94 and Rxe2x80x2 and Rxe2x80x2xe2x80x3 are both H.
In preferred compounds of formula I, R2 is H.
In preferred compounds of formula I, R3 and R4, are both H.
In preferred compounds of formula I, U is methylene.
In preferred compounds of formula I, Q is a group of formula IIa in which V is methylene, E and Exe2x80x2 are both ethylene and R5 is H.
In preferred compounds of formula I, T is phenyl or naphthyl, each of which may be optionally substituted by one or more substituents selected from an alkoxy group containing 1 to 3 carbon atoms, hydroxy, or halo (more preferably the substituent is methoxy). In more preferred compounds of formula I, T is phenyl optionally substituted by one or more substituents selected from an alkoxy group containing 1 to 3 carbon atoms, hydroxy, or halo (more preferably the substituent is methoxy). In especially preferred compounds of formula I, T is 2-methoxyphenyl or 2-hydroxyphenyl.
In one group of preferred compounds of formula I, both A and B are xe2x80x94Oxe2x80x94; g is 0, G1xe2x80x94G2xe2x80x94G3 are xe2x80x94NHxe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94NHxe2x80x94C(CO2C2H5)xe2x95x90CHxe2x80x94; xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94; Sxe2x80x94CHxe2x95x90C(Cl)xe2x80x94; xe2x80x94NHxe2x80x94Nxe2x95x90CHxe2x80x94; xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94; or xe2x80x94Oxe2x80x94CH2Oxe2x80x94; R2 is H; R3 and R4 are both H; U is methylene; Q is a group of formula IIa in which V is methylene, E and Exe2x80x2 are both ethylene and R5 is H; and T is phenyl optionally substituted by hydroxy or by one or more alkoxy groups each containing 1 to 3 carbon atoms. More preferably, G1xe2x80x94G2xe2x80x94G3 are xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94. Most preferably G1xe2x80x94G2xe2x80x94G3 are xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94.
In another group of preferred compounds of formula I, both A and B are xe2x80x94Oxe2x80x94; g is 0; G1xe2x80x94G2xe2x80x94G3 are xe2x80x94N(Rxe2x80x2)xe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94 wherein Rxe2x80x2 is H, Rxe2x80x3 is H or alkoxycarbonyl in which the alkoxy group contains 1 to 3 carbon atoms, and Rxe2x80x3 is H or halo; R2, R3 and R4 are each H; U is methylene; Q is a group of formula IIa in which V is methylene, E and Exe2x80x2 are both ethylene and R5 is H; and T is phenyl optionally substituted by hydroxy or one or more alkoxy groups.
In another group of preferred compounds of formula I, both A and B are xe2x80x94Oxe2x80x94; g is 0; G1xe2x80x94G2xe2x80x94G3 are xe2x80x94Sxe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94 wherein Rxe2x80x3 is H or alkoxycarbonyl in which the alkoxy group contains 1 to 3 carbon atoms, and Rxe2x80x2xe2x80x3 is H or halo; R2, R3 and R4 are each H; U is methylene; Q is a group of formula IIa in which V is methylene, E and Exe2x80x2 are both ethylene and R5 is H; and T is phenyl optionally substituted by hydroxy or one or more alkoxy groups.
In another group of preferred compounds of formula I, both A and B are xe2x80x94Oxe2x80x94; g is 0; G1xe2x80x94G2xe2x80x94G3 are xe2x80x94Oxe2x80x94C(Rxe2x80x3)xe2x95x90C(Rxe2x80x2xe2x80x3)xe2x80x94 wherein Rxe2x80x3 is H or alkoxycarbonyl in which the alkoxy group contains 1 to 3 carbon atoms, and Rxe2x80x2xe2x80x3 is H or halo; R2, R3 and R4 are each H; U is methylene; Q is a group of formula IIa in which V is methylene, E and Exe2x80x2 are both ethylene and R5 is H; and T is phenyl optionally substituted by hydroxy or one or more alkoxy groups.
In another group of preferred compounds of formula I, both A and B are xe2x80x94Oxe2x80x94; g is 0; G1xe2x80x94G2xe2x80x94G3 are xe2x80x94Oxe2x80x94C(Rxe2x80x2)(Rxe2x80x2)xe2x80x94Oxe2x80x94 wherein Rxe2x80x2 is H, R2, R3 and R4 are each H; U is methylene; Q is a group of formula IIa in which V is methylene, E and Exe2x80x2 are both ethylene and R5 is H; and T is phenyl optionally substituted by hydroxy or one or more alkoxy groups.
Compounds of formula I may exist as salts with pharmaceutically acceptable acids. The present invention includes all such salts. Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates, (xe2x88x92)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.
It will be understood that any group mentioned herein which contains a chain of three or more atoms signifies a group in which the chain may be straight or branched. For example, an alkyl group may comprise propyl, which includes n-propyl and isopropyl, and butyl, which includes n-butyl, sec-butyl, isobutyl and tert-butyl. The term xe2x80x98haloxe2x80x99 as used herein signifies fluoro, chloro, bromo and iodo.
Compounds of formula I and intermediates in their preparation contain one or more chiral centres, and exist in different optically active forms. When compounds of formula I and intermediates in their preparation contain one chiral centre, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. The enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallisation; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
When a compound of formula I contains more than one chiral centre it may exist in diastereoisomeric forms. The diastereoisomeric pairs may be separated by methods known to this skilled in the art, for example chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of compounds of formula I and mixtures thereof.
Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
Specific compounds of formula I are:-
N-(9-Chloro-2,3-dihydrothieno[3,2-f][1,4]-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
N-(2,3-Dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
Ethyl 2,3-dihydro-2-(N-{[1-(2-methoxyphenyl)piperid-4-yl]methyl}aminomethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate;
N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indazol-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
N-(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
2-{4-[(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)aminomethyl]piperidino}-phenol;
N-(7,8-Methylenedioxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
and pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates, or other mixtures of enantiomers.
Specific enantiomeric forms of compounds of formula I include:
(S)-N-(9-Chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
(S)-N-(2,3-Dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
Ethyl (S)-2,3-dihydro-2-(N-{[1-(2-methoxyphenyl)piperid-4-yl]methyl}aminomethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate;
(S)-N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)-1-[1-(2-methoxyphenyl)-piperid-4-yl]methylamine;
(S)-N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indazol-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine
(S)-N-(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine
(S)-2-{4-[(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)aminomethyl]-piperidino}phenol;
(S)-4-(7,8-Methylenedioxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine
and pharmaceutically acceptable salts thereof.
The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I or a salt thereof together with a pharmaceutically acceptable diluent or carrier.
As used hereinafter, the term xe2x80x9cactive compoundxe2x80x9d denotes a compound of formula I or a salt thereof. In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the pharmacists art.
Compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oil suspensions. The excipients used In the preparation of these compositions are the excipients known in the pharmacists art. Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 1 to 500 mg of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethyl- cellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
Compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Pharmaceutical compositions may also be administered parenterally (for example subcutaneously, intramuscularly, intradermally and/or intravenously (such as by injection and/or infusion)) in the known pharmaceutical dosage forms for parenteral administration (for example sterile suspensions in aqueous and/or oily media and/or sterile solutions in suitable solvents, preferably isotonic with the blood of the intended patient). Parenteral dosage forms may be sterilised (for example by micro-filtration and/or using suitable sterilising agents [such as ethylene oxide]). Optionally one or more of the following pharmaceutically acceptable adjuvants suitable for parenteral administration may be added to parenteral dosage forms: local anaesthetics, preservatives, buffering agents and/or mixtures thereof. Parenteral dosage forms may be stored in suitable sterile sealed containers (for example ampoules and/or vials) until use. To enhance stability during storage the parenteral dosage form may be frozen after filling the container and fluid (for example water) may be removed under reduced pressure.
Pharmaceutical compositions may be administered nasally in known pharmaceutical forms for such administration (for example sprays, aerosols, nebulised solutions and/or powders). Metered dose systems known to those skilled in the art (for example aerosols and/or inhalers) may be used.
Pharmaceutical compositions may be administered to the buccal cavity (for example sublingually) in known pharmaceutical forms for such administration (for example slow dissolving tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/or powders).
Compositions for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, for example paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol. Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The present invention also comprises a compound of formula I for use as a medicament.
The compounds of formula I or salts thereof or pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I or a salt thereof may be used to treat depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson""s disease, obesity, hypertension, Tourette""s syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer""s disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders, anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, and spasticity in human beings. Preferably, the compounds of formula I are used to treat psychoses, for example schizophrenia. Whilst the precise amount of active compound administered in such treatment will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history and always lies within the sound discretion of the administering physician, the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
A further aspect of the present invention provides the use of a compound of formula I in the manufacture of a medicament for treating depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson""s disease, obesity, hypertension, Tourette""s syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer""s disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, or spasticity in human beings. Preferably, there is provided a compound of formula I for use in the manufacture of a medicament for treating psychoses, for example schizophrenia.
The present invention also provides a method of treating depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson""s disease, obesity, hypertension, Tourette""s syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimers disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, or spasticity in human beings which comprises the administration of a therapeutically effective amount of a compound of formula I to a patient in need thereof, Preferably, the method is a method of treating psychoses, for example schizophrenia.
Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention. The processes are preferably carried out at atmospheric pressure, at a temperature in the range minus 80xc2x0 C. to 300xc2x0 C. more preferably in the range 0-200xc2x0 C., and most preferably in the range 20-150C. The substituents are as defined for formula I above unless otherwise stated.
Compounds of formula I in which Q is a group of formula IIa in which R5 is H, and V is (CH2)nwherein n is 1, 2 or 3 may be prepared by reaction of a compound of formula III 
in which m is 0, 1 or 2, with a compound of formula IV 
in which Z is a leaving group, for example toluene-4-sulphonyloxy, optionally in the presence of a suitable solvent, for example acetonitrile, optionally in the presence of a base, for example potassium carbonate, and optionally in the presence of a catalyst, for example potassium iodide.
Compounds of formula I in which U is methylene and Q is a group of formula IIa in which R5 is H, and V is (CH2)n wherein n is 1, 2 or 3, and Rxe2x80x3 and Rxe2x80x2xe2x80x3 are other than formyl may be prepared by reaction of a compound of formula V 
with a compound of formula III, followed by reduction of the intermediate imine with a suitable reducing agent, for example sodium borohydride.
Compounds of formula III and methods for their preparation are known (for example in WO95/07274).
Compounds of formula IV in which Z is toluene-4-sulphonyloxy may be prepared by reaction of a compound of formula VI 
with toluene-4-sulphonyl chloride, optionally in the presence of a base, for example pyridine or 4-dimethylaminopyndine.
Compounds of formula VI in which A and B are both xe2x80x94Oxe2x80x94, R2, R3 and R4 are all H, and U is methylene may be prepared by reaction of a compound of formula VII 
in which Z is a leaving group, for example chloro or toluene-4-sulphonyloxy, with a compound of formula VIII 
in a suitable solvent, for example water or dimethylformamide in the presence of a base, for example sodium hydroxide. When the appropriate enantiomerically pure form of a compound of formula VII, for example (R)-glycidyl 4-toluenesulphonate, is used, the single (S)-enantiomer of a compound of formula VI can be prepared.
Compounds of formula VI in which A and B are both xe2x80x94Oxe2x80x94, U is methylene, and R2, R3 and R4 are all H, may also be prepared by cyclisation of a compound of formula IX 
in which R is H or an alkyl group containing 1 to 4 carbon atoms, using a base, for example potassium carbonate.
Compounds of formula IX may be prepared by oxidation of compounds of formula X 
in which R is H or an alkyl group containing 1 to 4 carbon atoms, with a peroxyacid, for example 3-chloroperoxybenzoic acid.
Compounds of formula X may be prepared by alkylating compounds of formula XI 
in which R is H or an alkyl group containing 1 to 4 carbon atoms, with compounds of formula VII, in which Z is a leaving group, for example chloro or toluene-4-sulphonyloxy, In a suitable solvent, for example dimethylformamide, in the presence of a base, for example potassium carbonate. When the appropriate enantiomerically pure form of a compound of formula VII, for example (R)-glycidyl 4-toluenesulphonate, is used, the single (S)-enantiomer of a compound of formula VI can be prepared.
Compounds of formula VI in which A and B are both xe2x80x94Oxe2x80x94, U is methylene, R2, R3 and R4 are all H, and the group xe2x80x94G1xe2x80x94G2xe2x80x94G3xe2x80x94 contains the group Rxe2x80x3 which is as stated below, may be prepared as follows:
when Rxe2x80x3 is H or CO2Et, the compound of formula VI may be prepared by cyclisation of the appropriate compound of formula IX in the presence of potassium carbonate;
when Rxe2x80x3 is CO2H, the compound of formula VI may be prepared by hydrolysis of the corresponding compound of formula VI in which Rxe2x80x3 is CO2Et;
when Rxe2x80x3 is H, the compound of formula VI may also be prepared by decarboxylation of the corresponding compound of formula VI in which Rxe2x80x3 is CO2H;
when Rxe2x80x3 is CONH2, the compound of formula VI may be prepared by reaction of the corresponding compound of formula VI in which Rxe2x80x3 is CO2Et, CO2H, CO.Cl or CO.O.CO2Et with ammonia, in the presence, where appropriate, of an amide coupling agent such as carbonyl diimidazole;
when Rxe2x80x3 is CONMe2, the compound of formula VI may be prepared by reaction of the corresponding compound of formula VI in which Rxe2x80x3 is CO2Et, CO2H, CO.Cl or CO.O.CO2Et with dimethylamine, in the presence, where appropriate, of an amide coupling agent such as carbonyl diimidazole;
when Rxe2x80x3 is CHO, the compound of formula VI may be prepared by reduction of the corresponding compound of formula VI in which Rxe2x80x3 is CO2Et,
when Rxe2x80x3 is COMe, the compound of formula VI may be prepared by reaction of the corresponding compound of formula VI in which Rxe2x80x3 is CO2H with methyl lithium; and
when Rxe2x80x3 is CN, the compound of formula VI may be prepared by dehydration of the corresponding compound of formula VI in which Rxe2x80x3 is CONH2.
Compounds of formula VI in which A and U are methylene, B is xe2x80x94Oxe2x80x94, R2 is H and Rxe2x80x3 and Rxe2x80x2xe2x80x3 are H or cyano, may be prepared by reduction of a compound of formula XII 
with a reducing agent, for example boranedimethyl sulphide complex.
Compounds of formula XII may be prepared by reduction of a compound of formula XIII 
in which L is H with a reducing agent, for example hydrogen in the presence of a palladium-on-carbon catalyst.
Compounds of formula XIII in which L is H may be prepared by acid or base-catalysed hydrolysis of a compound of formula XIII in which L is an alkyl group containing 1 to 6 carbon atoms.
Compounds of formula XIII in which L is an alkyl group may be prepared by reaction of a compound of formula XI in which R is H with a compound of formula XIV 
in which L is an alkyl group containing 1 to 6 carbon atoms, in the presence of a base, for example 1,4-diazabicyclo[2.2.2]octane (DABCO).
Compounds of formula V may be prepared by oxidation of a compound of formula VI in which U is methylene with a suitable oxidising agent, for example pyridinium chlorochromate or by reduction of a compound of formula XV 
with a suitable reducing agent, for example sodium bis(2-methoxyethoxy)aluminium hydride in a solvent, for example toluene.
Compounds of formula XV in which A and B are both xe2x80x94Oxe2x80x94 may be prepared by reaction of a compound of formula XVI 
in which Y is a leaving group, for example bromo, and L is an alkyl group containing 1 to 6 carbon atoms with a compound of formula VII, in the presence of a base, for example potassium carbonate.
Compounds of formula XV in which A is methylene, B is xe2x80x94Oxe2x80x94, R2 is H and L is an alkyl group containing 1 to 6 carbon atoms may be prepared by reduction of a compound of formula XII in which L is an alkyl group containing 1 to 6 carbon atoms, with a suitable reducing agent, for example hydrogen in the presence of a palladium-on-carbon catalyst.
Compounds of formula I in which Q is a group of formula IIb may be prepared by reaction of a compound of formula IV in which Z is a leaving group, for example toluene-4-sulphonyloxy, with a compound of formula XVII 
in which Dxe2x80x2 is H, optionally in the presence of a base, for example potassium carbonate, and optionally in a solvent, for example acetonitrile.
Compounds of formula XVII in which Dxe2x80x2 is H may be prepared by deprotection of a compound of formula XVII in which Dxe2x80x2 is a protecting group, for example tert-butoxycarbonyl, for example by hydrolysis in the presence of an acid, for example trifluoroacetic acid.
Compounds of formula XVII in which Dxe2x80x2 is a protecting group may be prepared by reaction of a compound of formula XVIII 
in which Dxe2x80x2 is a protecting group, for example tert-butoxycarbonyl, with a haloaromatic compound, for example a 2-halopyridine such as 2-chloropyridine, optionally in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane.
Compounds of formula I in which Q is a group of formula IIc in which V is (CH2)nwherein n is 1, 2, or 3 may be prepared by reaction of a compound of formula XIX 
in which Dxe2x80x2 is H and m is 0, 1 or 2, with a compound of formula IV in which Z is a leaving group, for example toluene-4-sulphonyloxy, optionally in the presence of a base, for example potassium carbonate, and optionally in a solvent, for example acetonitrile.
Compounds of formula XIX in which Dxe2x80x2 is H may be prepared by deprotection of a compound of formula XIX in which Dxe2x80x2 is a protecting group, for example tert-butoxycarbonyl, for example by hydrolysis in the presence of an acid, for example trifluoroacetic acid.
Compounds of formula XIX in which Dxe2x80x2 is a protecting group may be prepared by reaction of a compound of formula XX 
in which Dxe2x80x2 is a protecting group, for example tert-butoxycarbonyl, and m is 0, 1 or 2, with a haloaromatic compound, for example a 2-halopyridine such as 2-chloropyridine, optionally in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane.
Compounds of formula IV in which G1xe2x80x94G2xe2x80x94G3 are xe2x80x94NHxe2x80x94CHxe2x95x90CHxe2x80x94 are known (J. Med. Chem., 1992,35, pg 3058).
Compounds of formula IV in which G1xe2x80x94G2xe2x80x94G3 are other than xe2x80x94NHxe2x80x94CHxe2x95x90CHxe2x80x94 may be prepared by methods analogous to that described above.
Compounds of formula I in which R5 is an alkyl group and Rxe2x80x3 and Rxe2x80x2xe2x80x3 are other than formyl may be prepared by alkylation of a compound of formula I in which R5 is H with for example formaldehyde and formic acid, or an aldehyde and a reducing agent such as sodium cyanoborohydride.
Compounds of formula XI in which R is H may be prepared by reaction of a compound of formula XXI 
with an N-arylformimidate ester of formula XXII 
in which Ra is H, an alkyl group containing 1 to 3 carbon atoms, an alkoxy group containing 1 to 3 carbon atoms, or halo, and Rb is an alkyl group containing 1 to 3 carbon atoms, for example ethyl N-(4-methoxyphenyl)formimidate, followed by hydrolysis of the intermediate imine in the presence of an acid.
Compounds of formula XI in which Rxe2x95x90H and G1xe2x80x94G2xe2x80x94G3 represents xe2x80x94Oxe2x80x94C(Rxe2x80x2)2xe2x80x94Oxe2x80x94 may be prepared by reaction of a compound of formula XXIII 
with a lithiating agent, for example sec-butyllithium, followed by a formylating agent, for example N,Nxe2x80x94dimethylformamide, followed by hydrolytic work-up.
Compounds of formula XXIII may be prepared by reaction of compounds of formula XXI with diethylcarbamoyl chloride in the presence of a base, for example sodium hydride.
Compounds of formula I in which the group T bears a hydroxy substituent may be prepared by dealkylation of a corresponding alkoxy substituted compound, by reaction with a dealkylating agent, for example pyridine hydrochloride.
Compounds of formula I in which G1xe2x80x94G2xe2x80x94G3 represents xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94 may be prepared by dechlorination of a corresponding compound in which G1xe2x80x94G2xe2x80x94G3 represents xe2x80x94Sxe2x80x94CHxe2x95x90CClxe2x80x94 by, for example, reaction with hydroiodic acid.
The ability of compounds of formula I to interact with 5-hydroxytryptamine (5-HT) receptors has been demonstrated by the following test which determines the ability of the compounds to inhibit tritiated ligand binding to 5-HT receptors in vitro and in particular to 5-HT1A receptors.
Hippocampal tissue from the brains of male Charles River CD rats weighing between 150-250 g were homogenised in ice-cold 50 mM Tris-HCl buffer (pH 7.7) when measured at 25xc2x0 C., 1:40 w/v) and centrifuged at 30,000 g at 4xc2x0 C. for 10 minutes. The pellet was rehomogenised in the same buffer, incubated at 37xc2x0 C. for 10 minutes and centrifuged at 30,000 g at 4xc2x0 C. for 10 minutes. The final pellet was resuspended in 50 mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl2, 0.1% L-ascorbic acid and 10 xcexcM pargyline hydrochloride (equivalent to 6.25 mg wet weight of tissue/ml) and used immediately in the binding assay. Aliquots (400 xcexcl; equivalent to 2.5 mg wet weight of tissue/tube) of this suspension were added to tubes containing the ligand (50 xcexcl; 2 nM) and distilled water (50 xcexcl; total binding) or 5-HT (50 xcexcl; 10 xcexcM; non-specific binding) or test compound (50 xcexcl; at a single concentration of 10xe2x88x928 M or at 10 concentrations ranging from 10xe2x88x9211xe2x88x9210xe2x88x923 M). The ligand was [3H]8-hydroxy-2-(dipropylamino)tetralin ([3H]8-OH-DPAT) and the mixture was incubated at 25xc2x0 C. for 30 minutes before the incubation was terminated by rapid filtration.
The filters were washed with ice-cold Tris-HCl buffer and dried. The filters were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting. The percentage displacement of specific binding of the tritiated ligand was calculated for the single concentration (10xe2x88x926 M) of test compound. Displacement curves were then produced for those compounds which displaced xe2x89xa750% of specific binding of the tritiated ligand at 10xe2x88x926 M using a range of concentrations of the compound. The concentration which gave 50% inhibition of specific binding (IC50) was obtained from the curve. The inhibition coefficient Ki was then calculated using the formula       K    i    =            I      ⁢              xe2x80x83            ⁢      C50              1      +              (                              [            ligand            ]                    /                      K            D                          )            
in which [ligand] is the concentration of the tritiated ligand used and KD is the equilibrium dissociation constant for the ligand.
The ability of compounds of formula I to interact with dopamine receptors has been demonstrated by the following test which determines the ability of the compounds to inhibit tritiated ligand binding to dopamine receptors in vitro and in particular to the D2-like dopamine receptors.
Striatal tissue from the brains of male Charles River CD rats weighing between 140-250 g were homogenised in ice-cold 50 mM Tris-HCl buffer (pH 7.7 when measured at 25xc2x0 C.) and centrifuged at 40,000 g for 10 minutes. The pellet was resuspended in Tris salts buffer (50 mM Tris-HCl buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2 with the addition of 6 mM ascorbic acid; pH 7.7 when measured at 25xc2x0 C.), and again centrifuged at 40,000 g for 10 minutes. The final pellet was stored at xe2x88x9280xc2x0 C. Before each test the pellet was resuspended in Tris salts buffer (equivalent to 2 mg wet weight of tissue/ml). Aliquots (720 xcexcl; equivalent to 1.44 mg wet weight of tissue/tube) of this suspension were then added to tubes containing the ligand (40 xcexcl; 1 nM) and Tris salts buffer (40 xcexcl; total binding) or spiroperdol (40 xcexcl; 10 nM; non-specific binding) or test compound (40 xcexcl; at a single concentration of 10xe2x88x926M or at 6 concentrations ranging from 10xe2x88x9211xe2x88x9210xe2x88x926M). The ligand was tritiated (S)-sulpiride and the mixture was incubated at 4xc2x0 C. for 40 minutes before the Incubation was terminated by rapid filtration.
The filters were washed with ice-cold Tris-HCl buffer and dried. The filters were punched out in to vials, scintillation fluid added and were left for about 20 hours before being counted by scintillation spectrophotometry. The percentage displacement of specific binding of the tritiated ligand was calculated for the single concentration (10xe2x88x926M) of test compound. Displacement curves were then produced over a range of concentrations for those compounds which displaced xe2x89xa750% of specific binding of the tritiated ligand at 10xe2x88x926M. The concentration which gave a 50% inhibition of specific binding (IC50) was obtained from the curve. The inhibition coefficient Ki then calculated using the formula       K    i    =            I      ⁢              xe2x80x83            ⁢      C50              1      +              (                              [            ligand            ]                    /                      K            D                          )            
in which [ligand] is the concentration of the tritiated ligand used and KD is the equilibrium dissociation constant for the ligand.
The Ki values obtained in the above tests for 5-HT1A and D2-like binding for each of the final products of the Examples hereinafter are given in Table I below.
Advantageous compounds of the present invention have a Ki of less than 100 nM for 5-HT1A or a binding affinity for 5-HT1A of greater than 90% at 10xe2x88x926M and a Ki of less than 100 nM for D2-like receptors or a binding affinity for D2-like receptors of greater than 90% at 10xe2x88x926M.